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  • Review Article
  • Published:

T cells out of control—impaired immune regulation in the inflamed joint

Nature Reviews Rheumatology volume 9, pages 34–42 (2013)Cite this article

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Abstract

Since the discovery of FOXP3+ regulatory T (TREG) cells over 15 years ago, intensive research has focused on their presence, phenotype and function in autoimmune disease. Whether deficiencies in TREG cells underlie autoimmune pathology and whether, or how, therapeutic approaches based on these cells might be successful is still the subject of debate. The potential role of TREG-cell extrinsic factors, such as proinflammatory cytokines and resistance of effector T cells to suppression, as the cause of regulatory defects in chronic autoimmune inflammation is an intensive area of research. It is now clear that, at the site of inflammation, antigen presenting cells (APCs) and proinflammatory cytokines drive effector T cell skewing and plasticity, and that these T cells can become unresponsive to regulation. In addition, expansion and function of TREG cells is affected by the inflammatory environment; indeed, new data suggest that, in certain conditions, TREG cells promote inflammation. This Review summarizes the latest findings on changes in effector T cell homeostasis in autoimmune disease and focuses on how mechanisms that normally regulate these cells are affected in the inflamed joints of patients with arthritis. These findings have important clinical implications and will affect the development of new therapeutic strategies for autoimmune arthritis.

Key Points

  • The study of immune regulation at the site of inflammation is required to improve our understanding of autoimmune pathology

  • At the site of autoimmune inflammation, proinflammatory mediators interfere with T-cell regulation and may induce T-cell plasticity

  • Regulatory T (TREG) cells are less functional, or might even become pathogenic, in an autoimmune inflammatory environment, which should be kept in mind when developing TREG-cell-based therapies

  • Resistance of effector T cells to suppression markedly contributes to the disturbed immune balance in the inflamed joints of patients with arthritis

  • In autoimmune inflammation, a perpetuating loop exists in which antigen presenting cells (APCs) instruct T-cell differentiation and function, and effector T cells promote and shape the infiltration and differentiation of APCs

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Figure 1: Reciprocal development of peripherally induced TREG and TH17 cells.
Figure 2: The main CD4+ T-cell subsets in synovial inflammation.
Figure 3: Perpetuating loop of uncontrolled synovial inflammation.

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Acknowledgements

F. van Wijk is supported by a Veni grant from the Dutch Organization for Scientific Research (NWO). B. J. Prakken is supported by the Dutch Rheumatology Foundation.

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  1. Department of Paediatric Immunology, Center for Molecular and Cellular Intervention, University Medical Centre Utrecht, PO Box 85090, Utrecht, 3508 AB, The Netherlands

    Ellen J. Wehrens, Berent J. Prakken & Femke van Wijk

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Wehrens, E., Prakken, B. & van Wijk, F. T cells out of control—impaired immune regulation in the inflamed joint. Nat Rev Rheumatol 9, 34–42 (2013). https://doi.org/10.1038/nrrheum.2012.149

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  • DOI: https://doi.org/10.1038/nrrheum.2012.149

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